基于Pax8通路的碘过量致甲状腺肿大机制研究

Goiter induced by high iodine (GHI) is one of the most common health problems caused by excessive iodine，but the mechanism is uncertain and controversial. The questions caused by GHI are restricting the implementation of USI. In the past, we traditionally thought that GHI was obviously different from goiter induced by iodine deficiency which characterized by proliferation of thyroid follicle cells. In GHI, instead of proliferation, redundancy of thyrocolloid generation and the abnormal thyrocolloid release were the main causes. GHI could alleviate itself as time going. So we always underestimate the impact of GHI on public. But the recent evidences indicated that follicle cells also proliferated in GHI. The high iodine exposure could increase the prevalence of goiter, even induce thyroid carcinoma. It aroused controversy about the real mechanism of GHI. GHI becomes a problem of public health. It is also an important reason for the public denounce USI. In the previous study, we found a relationship between the goiter and gene polymorphism of Pax8 gene. We supposed that Pax8 play a critical role in the development of GHI. This programme, basing on the controversy on GHI, is planning to adopt the animal model and population investigation to study the influence of high iodine exposure on the regulation of Pax8 to the proliferation of thyroid follicle cells and generation and release of thyrocolloid. Then, use the knock-out animal model to verify our hypothesis. We look forward to illustrate the mechanism on proliferation of follicle cells and the metabolism of thyrocolloid in GHI by this project. And we hope it can supply data for the exploring of drugs and measurements to prevent and cure diseases induced by high iodine exposure, and finally guarantee the scientificity and safety of the implementation of USI.

碘过量导致的甲肿是高碘暴露中最常见的问题之一，但其机制存在争议，高碘性甲肿引发的质疑也严重影响USI的持续实施。此前有研究认为，高碘性甲肿是由于甲状腺胶质产生过多、释放障碍导致的胶质性肿大，可随暴露时间的延长逐渐减轻，因此对于高碘暴露缺乏重视。但近年也有研究显示，高碘性甲肿还存在甲状腺滤泡细胞增殖分化，高碘暴露可导致人群甲肿率明显增高，甚至诱发癌症，已成为一个公共卫生问题，也是导致民众质疑USI的重要原因。本研究前期发现甲肿与Pax8基因多态性存在关联，猜想Pax8在高碘性甲肿中具有关键作用。本项目基于高碘性甲肿机制的争论，拟通过高碘性甲肿动物模型结合高水碘地区人群调查，以Pax8通路为线索研究高碘暴露对甲状腺滤泡增殖及胶质产生和释放的影响，并采用转基因动物模型验证猜想，以期从细胞增殖和胶质代谢的角度阐明碘过量致甲肿的相关机制，为研究高碘性甲肿的防治方法提供依据，保障USI的科学合理实施。

随着USI的持续实施，我国居民碘营养状况得到了显著改善，随之出现的碘摄入过量问题也越来越受关注，其中高碘性甲肿是高碘暴露中最常见的问题之一。本研究通过高碘性甲肿动物模型结合高水碘地区人群调查，以Pax8及相关作用途径为关注点，采用转录组和代谢组学方法，探讨高碘暴露与甲状腺肿大的关联，并从甲状腺激素合成与分泌的角度探索高碘性甲状腺肿的相关机制。本项目完成Pax8基因敲减小鼠模型的构建与评价，人群研究共调查不同碘水平成人（2655人）和儿童（2224人）人群的甲状腺健康信息，其中获得成人甲肿患者人数为776人，儿童甲肿患者人数为212人，比原计划125人超额690.4%完成，研究结果显示，高碘暴露可增加甲状腺肿大发生的风险，尤其在当前居民碘营养得到大幅改善和提升的背景下，应注意避免过量碘摄入造成的甲肿问题。Pax8是甲状腺发育成熟过程中的重要调节蛋白，高碘暴露可能通过影响胶质蛋白的合成及激素释放诱发甲肿的，同时高碘暴露可能提高甲状腺特异蛋白TG、TPO的免疫原性，增加自身免疫性甲状腺疾病的患病风险，进一步促进甲肿的发生和发展。本项目目前已发表SCI论文2篇，中文论文3篇，培养硕士研究生1名，本科生1名，晋升副教授1名，圆满完成项目计划工作目标。